The major drawback to current and-ADS therapy is the emergence of drug resistant mutants of HIV- 1. In the quest for novel HIV- 1 specific inhibitors, our strategy has been to target the conserved non-translated 5' region of the viral genome that contains multiple regulatory elements such as TAR, PBS, A-loop, DIS etc which are critical for viral replication. Selective intervention of the function of these regulatory regions may have profound therapeutic potential in blocking viral infection. We have identified a number of leading polyamide nucleotide analogs (PNA) which can successfully block the function of these targets in vitro. The major thrust of this proposal is to conjugate these leading PNAs with a number of membrane transporting peptides in order to identify the most efficient biodelivery system thus enhancing the functional efficacy of these compounds. Each PNA-peptide conjugate will be examined in-depth with respect to its uptake kinetics, functional efficacy, cytotoxicity and antiviral activity in cell cultures. The leading PNA-peptide conjugates will also be tested for their pharmacokinetic behavior, tissue distribution and toxicological properties in animal models. This will be followed by subjecting these compounds to pre-clinical trial on hu-SCID mice model reconstructed with human PBL. These studies will provide invaluable information on this class of compounds, which may help in the development of effective multi-pronged inhibitors of high therapeutic index. The following specific aims are proposed. (1) To design and synthesize potential PNA - MTD peptide conjugates targeted to the critical regions of HIV- 1 RNA genome. (2) To evaluate the biodelivery and functional efficacy of PNA- transporter peptide conjugates.; (3) To evaluate the antiviral efficacy and cytotoxicity of PNA-peptide conjugates in cell culture. (4) To carry out pharmacokinetic studies, tissue distribution analysis, and toxicological evaluation of leading PNA-transporter peptide formulations.; (5) To determine the immune response of potential PNA-MTD peptide conjugates.; (6) To evaluate the antiviral efficacy of PNA-peptide conjugates using SCID-hu mice model.